The present invention relates to a sintered tricalcium phosphate implant for filling bone cavities and for fixing bone fragments in a living body, and to a process for producing such a sintered, tricalcium phosphate implant. The present invention is also directed to an implant system for filling bone cavities and for fixing bone fragments within a living body.
Various compositions for implantation within bone are known, such compositions being used, e.g., for filling cavities within bone in a living body, affixing or cementing implants already disposed within a cavity of bone to the bone in a living body, anchoring joint endoprotheses, or for similar implantation purposes. Such bone implant compositions or cements may be inserted into the living body in the form of a plastic paste, which subsequently hardens due to polymerization in situ. Such a paste may be prepared by mixing primary polymers such as powdery methyl methacrylate homopolymers or copolymers, with suitable liquid monomers such as methyl methacrylate, along with a catalyst system, and, if necessary, radiopaque media for identifying the cement within the living body. Hardening naturally occurs due to polymerization of the monomer.
German Pat. Appl. DE-A No. 22 29 702 discloses a bone cement of polymethyl methacrylate and a monomer compound of methyl methacrylate and methacrylic acid esters of higher alcohols, along with a catalyst system of benzoyl peroxide and dimethyl-p-toluidine.
The inclusion of antibiotics in such bone implantation compositions or cements, for the purpose of preventing infection along the boundary surface between the cement and the bone within the living body, is also known. For example, Bild der Wissenschaft, 10, (1979) 114-126 discloses bone implants made of tricalcium ceramic material, used as a bone substitute, combined with antibiotics as a medicine depot at the fracture surface. According to DE-A No. 20 22 117, antibiotics which may be included in a bone implant composition or cement include penicillin, gentamycin and tetracycline. The antibiotic is initially released from the hardened bone cement at a relatively high concentration, thus obtaining the requisite bactericidal or bacteriostatic effect. However, a subsequent drop in antibiotic concentration within the bone implant or cement results in a lower release rate of antibiotic, this rate remaining constant over a longer period of time. Thus even though certain long-term or depot action is attained, the effective antibiotic concentration remains too low.
DE-B No. 25 11 122 discloses discloses an initial product for preparation of bone cement or implant material, which in addition to a gentamycin compound, contains either pulverulent copolymers of methyl methacrylate or monomeric methyl methacrylate as the principle constituent, as well as gentamycin hydrochloride and/or gentamycin hydrobromide, or a mixture of gentamycin sulfate with sodium chloride, potassium chloride, sodium bromide and/or potassium bromide. The resulting initial product for the preparation of bone cement releases the antibiotic at increased concentration than in the previously-noted products. However, the effectiveness of the antibiotic is not maintained over a long period of time.
EP-A-1 No. 0 003 979 (U.S. Pat. No. 4,322,398) describes an implantable pharmaceutical depot and a process for the production thereof. The base of this known implant is formed by a calcium phosphate matrix which is impregnated with a therapeutically-active component, and which also contains an auxiliary agent for generating the depot effect. Two possible variations for this combination of matrix, active component, and auxiliary agent are disclosed.
According to the first possible variation disclosed in EP-A-1 No. 0 003 979, the therapeutically active component is encapsulated with a polymer and subsequently inserted into the matrix. The encapsulated therapeutically-active component is is thus absorbed into the pores of the sintered matrix. However, the available volume (i.e. the volume within these pores) is thus partially filled by the polymer encapsulating the therapeutically active component, so that this volume is lost for the absorption of the active component itself. If the depot effect is set at a different timing by increasing the volume of the encapsulating polymer, then the available concentration of the active component is impaired to a greater or lesser degree.
According to the second possible variation disclosed in EP-A-1-0 003 979, instead of inserting the encapsulated active component into the finished matrix, the pulverized mixing components forming the matrix material along with the therapeutically active component, are all coated (i.e. all components forming the depot are coated at once). However, this is not suitable for producing a sintered molded implant, since the therapeutically active component and the auxiliary agent would both be destroyed by the heating required for the subsequent sintering process. Instead, a solid material is created by this second variation which is merely held together by the auxiliary agent, does not have the requisite strength for bone implantation, and where the calcium phosphate powder forming the matrix will not offer a supporting surface for the osteoblasts, which is essential for addition to, or implantation in bone within a living body.
Philips Technishe Rundschau Vol. 37 No. 9/10 (1977/78) 225-257, in explaining the suitability of calcium phosphate for implantation purposes, describes the possibility of producing specific porosities while sintering the bone implant. In order to exclusively generate small pores within the sintered implant apart from large pores therein, a specific quantity of hydrogen peroxide is added to the calcium phosphate prior to sintering, according to this reference. This chosen quantity of hydrogen peroxide, along with the heating rate of sintering, influence the macroporosity that occurs within the sintered article, while the microporosity occurring therein is influenced by other parameters.
DE-AL No. 27 25 665 (U.S. Pat. No. 4,230,455) discloses a baked and molded article formed of hydroxyapatite which has a fibrous insertion surrounded by hydroxyapatite with an additive, such as AlF.sub.3. However, it is not disclosed in this reference whether there is any controllable depot affect of an active component. DE-AL No. 27 56 256 discloses a gel-type auxiliary agent for coating and/or filling bone defects, which contains at least one polysaccharide and which serves to create a sterile seal between the surface of a wound and the implant during the healing process.
Thus there are several drawbacks and disadvantages in the prior art concerning implantation within bone in a living body, notably with the effective, controlled release of a therapeutically active ingredient during the subsequent bone formation or healing process over a period of time.